Treatment of Adult Patients with the Modified Protocol of the International Consortium on Acute Promyelocitic Leukemia (IC-APL)

Introduction

Acute promyelocytic leukemia (APL) with PML/RARA rearrangement is currently classified by the WHO as part of the group of acute myeloid leukemia with recurrent genetic abnormalities. Therapeutic improvements in chemotherapy protocols containing trans-retinoic acid (ATRA) have achieved complete response rates close to 90% and long-term relapse free survival curves of 85%.

The treatment protocol of the International Consortium on Acute Promyelocytic Leukemia (IC-APL), which started in 2006, sought to improve rates of complete remission and survival in developing countries through a risk-based protocol and the implementation of daunorubicin instead of idarubicin. Recently the results of that multicenter study were published.

Methods

A retrospective cohort of patients with APL was studied at the Acute Leukemia Clinic of the Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico; from January 2007 to June 2013.

All APL patients were recruited from 2006 to 2013. Diagnosis of APL was established based on the recommendations of the 2000 WHO and subsequently 2008.

The original IC-APL chemotherapy scheme was administered. Some minor modifications to the original protocol were made: we did not search for minimal residual disease neither identify the PML / RARA isoforms at diagnosis and prophylactic intrathecal chemotherapy in high-risk patients was applied (4-6 dose cytarabine 60mg and methotrexate 12.5mg), monthly, once the consolidation therapy was finished. Patients who relapsed received rescue therapy and autologous HCT. Allogeneic HCT was performed in advaced stages.

Results

Of the 18 patients evaluated 11 were women (61.1%). The median age at diagnosis was 40 years, (range 21-74 years). It should be noted that 16.6% had more than 65 years. The risk classification showed 27.8% of cases as low risk, 55.6% intermediate and 16.7% of high risk.

At diagnosis 22.2% of patients met the criteria for disseminated intravascular coagulation. Morphological characteristics of BMA were analyzed; in 17 patients (94.1%) BMAs were classified as classic and in one patient it was considered variant-type. Sixteen patients underwent immunophenotyping at diagnosis, 100% of which reported a classic pattern immunophenotype CD34 (-) HLA-DR (-), CD13 (+) CD33 (+), myeloperoxidase (+). The t (15, 17) (q22, q21) was demonstrated by either FISH or karyotype in 94.4% of patients and in one patient the PML/RARA rearrangement could only be demostrated by PCR.

Of the 18 patients, 17 achieved complete hematologic remission (94.4%) at a median of 42 days (range 34-158 days). One patient died during induction and this patient presented multiple comorbidities.

No serious complications were seen in 66.7% of patients during induction, 22.2% had grade 3-4 infection and 11.1% non-hematologic adverse events and one patient had subarachnoid hemorrhage and vasculitis.

The rates of severe neutropenia and fever during induction was 61.1%. ATRA syndrome was identified in 22.2% of patients.

Only 15 patients in complete hematologic remission could be analyzed by FISH or cytogenetics, of which 100% were in complete cytogenetic remission.

In the 17 patients who achieved complete remission, 14 received all the programmed consolidation chemotherapy. The incidence of febrile neutropenia during consolidation was 29.4%, contrasting with 61.1% after induction. No deaths during consolidation phase were seen.

Bone marrow relapse was documented in 5.9%. This patient underwent autologous HCT and subsequently died of disease progression.

Of all patients, two died (11.1%), one in bone marrow aplasia after induction (5.5%) and the other in disease progression post-autologous HCT (5.5%). Median survival has not been reached.

Conclusions

As far as we know this is the first reported series of patients treated with the modified-IC-APL protocol after the original publication in 2013. Longer follow-up is required for survival analysis (median not reached). Implementation of quantitative RT-PCR analysis for minimal residual disease and timely detection of molecular relapse is desirable.